It is well documented that hypogonadism (testosterone deficiency) is associated with obesity, metabolic syndrome, reduced libido, erectile dysfunction and orgasmic dysfunction 1, and that testosterone therapy in these men improves cardiometabolic and sexual function.2,3

However, concern remains that testosterone therapy may worsen lower urinary tract symptoms (LUTS) by possibly causing benign prostatic hyperplasia (BPH) 4, although few major adverse events have been reported.

Here we summarize the results from a study published in the Journal of Urology, which examined the effects of long-term testosterone therapy in men with testosterone deficiency on sexual and urinary function, and quality of life.5

Key Points

Despite a lack of evidence, there have been stated concerns that testosterone therapy can pose a risk to men suffering with LUTS / BPH.

Compared to non-treated hypogonadal men, testosterone therapy for up to 8 years:

improves LUTS, as shown by reductions in IPSS and post-void bladder volume.

The greatest improvement in erectile function, LUTS and AMS scores occurred during the first 2 years of testosterone treatment, and benefits continue to manifest years after therapeutic testosterone levels have been achieved.

What is known about testosterone, sexual and urinary function

The 2010 Endocrine Society Clinical Practice Guideline cautioned against the use of testosterone replacement therapy in patients with severe LUTS.6 However, it has been pointed out that LUTS is in part due to reduced testosterone levels.7 Support for this comes from six recent randomized controlled trials which all showed that testosterone therapy in patients with LUTS does not worsen LUTS symptoms - measured by the validated International Prostate Symptom Score (IPSS) questionnaire - compared to placebo.8-13 Even in men with severe LUTS, no differences in IPSS were seen in men receiving testosterone replacement therapy vs. placebo.13 Notably, there was actually a small improvement in IPSS scores in the testosterone treated group.13

A meta-analysis of 14 clinical trials investigating the effect of testosterone therapy on LUTS reported that the change in IPSS was similar among men receiving testosterone therapy versus placebo, suggesting that testosterone treatment does not worsen LUTS.14

A systematic review of 35 trials evaluating the effects of testosterone therapy on LUTS and prostate volume found that in the majority of trials there was no significant prostate growth due to testosterone therapy.15 Studies of men with baseline mild LUTS demonstrated either no change or an improvement in symptoms after treatment. There was a lack of relevant urodynamic studies. Trials of men with the metabolic syndrome demonstrated uniform improvement in lower urinary tract symptoms. It was concluded that there is minimal support for a causative link between testosterone therapy, de novo LUTS or worsening of existing LUTS or prostate volume.15 Notably, this systemic review found an absence of high quality evidence that would support guideline recommendations that testosterone therapy is relatively contraindicated in men with severe LUTS.15 Future clinical trials with more inclusive voiding criteria are needed.

What this study adds

The study in the Journal of Urology was an observational, prospective, cumulative registry study in 656 men with a mean age of 61 years who had total testosterone levels of 12.1 nmol/L or less, and symptoms of hypogonadism.5 The testosterone treated group, comprising 360 men, received parenteral testosterone undecanoate 1,000 mg/12 weeks for up to 10 years. The 296 men who elected against testosterone therapy served as controls. From each group 82 patients were propensity matched for age, waist circumference and body mass index, resulting in 82 matched pairs of 164 men.

Results showed that testosterone therapy significantly decreased IPSS and post-void bladder volume. There were also significant improvements in the Aging Males' Symptoms Scale and the IIEF-EF (International Index of Erectile Function-Erectile Function) domain. In untreated hypogonadal men voiding and erectile function deteriorated with continued follow-up. Notably, the significant improvements in LUTS were assessed both subjectively by IPSS and objectively by reductions in ultrasound-measured post-void bladder volume.

The effect of testosterone on these outcomes is described in more detail below.

Lower Urinary Tract Symptoms

As shown in figure 1, testosterone treated men had a marked, progressive, sustained and significant reduction in IPSS. The decrease in IPSS was largest during the first 2 years. In contrast, in the untreated group IPSS gradually increased. Even after adjustment for baseline age, weight, waist circumference, fasting blood glucose, blood pressure, lipids and AMS score there were significant differences in IPSS throughout the follow-up period.

Figure 1: Improvement in IPSS in testosterone treated men compared to untreated men during 8-year follow-up.

At baseline 50% of the patients in the testosterone treated group had mild symptoms (IPSS score 0 to 7) and 50% had moderate symptoms (IPSS 8 to 19). In the control group 91.5% of the men had mild symptoms and 8.5% had moderate symptoms, indicating that non-testosterone treated men were in a better situation at baseline. At the last visit all patients in the testosterone group had improved to the mild category. In contrast, among the non-testosterone treated men, 61% had mild symptoms and 39% had moderate symptoms at the last visit, and thus experienced a worsening of LUTS symptoms.

Post-Void Bladder Volume

As shown in figure 2, there was a progressive and significant reduction in post-void bladder volume in testosterone treated men, which was parallel to the reduction in IPSS. In contrast, in the untreated group post-void bladder volume gradually increased.

Figure 2: Improvement in post-void residual bladder volume in testosterone treated men compared to untreated men during 8-year follow-up.

Figure 3 shows the significant improvement in erectile function in testosterone treated men, as demonstrated by a significant increase in IIEF-EF scores. In contrast, in the untreated group there was a progressive deterioration in erectile function, as demonstrated by a significant decrease in IIEF-EF scores over time.

Figure 3: Improvement in IIEF-EF in testosterone treated men compared to untreated men during 8-year follow-up.

A significant reduction in AMS scores – indicating improvement in symptoms potentially related to testosterone deficiency – was observed in testosterone treated men, as shown in figure 4. The decrease in AMS was steep during the first 2 years and then remained low throughout follow-up. In contrast, AMS increased slightly in the untreated group.

Figure 4: Improvement in AMS scores in testosterone treated men compared to untreated men during 8-year follow-up.

Mean prostate volume in testosterone treated men slightly increased from 31.4 to 33.2 mL, while it remained stable in untreated men. PSA remained unchanged in both testosterone treated and untreated men.

Commentary

Despite a lack of evidence, there have been stated concerns that testosterone therapy can pose a risk to men suffering with LUTS / BPH.16 Contrary to the previous dogma that prostatic growth is directly proportional to testosterone levels, emerging research has suggested that a lack of testosterone may be a risk factor for LUTS and BPH.17 Testosterone therapy improves conditions that are associated with worsening of LUTS, such as the metabolic syndrome and prostatic inflammation.16 Testosterone can also help by increasing expression and activity of nitric oxide synthase and smooth muscle relaxation.17

The present study concluded that long-term testosterone therapy in hypogonadal men significantly improves urinary and sexual function, and quality of life, while untreated men experience worsening of these outcomes.5 These results confirm previous reports of significant improvements in voiding symptoms or LUTS following testosterone therapy.18-22 This refutes old concerns about testosterone therapy and LUTS / BPH by showing that long-term testosterone therapy – contrary to common opinion – improves LUTS even in men with moderate symptoms (IPSS 8 to 19), while mild LUTS worsen over time in untreated hypogonadal men.

It should be highlighted that the greatest improvement in erectile function, LUTS and AMS scores occurred during the first 2 years of testosterone treatment.5 The greatest elevation in testosterone levels occurred during the first year of treatment; hence, benefits continue to manifest years after therapeutic testosterone levels have been achieved.5 This underscores the importance of considering the time course for onset and maximal expression of benefits with testosterone therapy. When starting testosterone treatment, the US Endocrine Society 6 and Canadian 23 clinical practice guidelines recommend a 3-month trial of treatment, while the International Society for Sexual Medicine Guideline 24 and individual experts 25 recommend that clinicians consider a minimum period of 6 months when assessing response. As demonstrated in this study, where marked improvements were seen in erectile function, LUTS and AMS scores over the first 2 years of treatment, even 6 months may be a too short time period to evaluate the efficacy of testosterone treatment.